1. Field of the Invention
The present disclosure relates to a novel vascular leakage inhibitor.
2. Description of the Related Art
The disruption of endothelial barrier integrity leading to increased vascular permeability contributes to many pathological processes, including various inflammatory diseases, acute lung injury, and diabetic retinopathy. Endothelial permeability is tightly controlled by cell-cell junctions, including adherens junctions (AJs) and tight junctions (TJs), between neighboring endothelial cells. TJs consist of a number of proteins, including occludin, claudins, junctional adhesion molecules (JAMs), and zonula occludens (ZOs). Occludin, claudins, and JAMs are major integral transmembrane proteins with adhesive properties, and are believed to be responsible for the formation of a tight seal between two opposing endothelial membranes of adjacent cells (Int J Biochem Cell Biol. 2004 July; 36(7):1206-37). Occludin and claudins form homodimeric bridges, and ZOs and cingulin connect these integral transmembrane proteins to actin filaments (J Cell Biol. 1999 Dec. 27; 147(7):1569-82). Dynamic regulation of perijunctional actin has been suggested to control paracellular permeability by affecting the stability of TJs closely connected to the actin cytoskeleton, either directly or indirectly (Anna Rev Physiol. 1998; 60:143-59). In fact, there are ample ultrastructural evidences to implicate the temporal expression, dynamic organization, and spatial distribution of the actin cytoskeleton in the alteration of TJ complexes under various conditions (Physiol Rev. 2006 January; 86(1):279-367). Therefore, actin is likely to play a critical role in modulating the integrity of TJs, and thus, endothelial permeability.
The reorganization of the actin cytoskeleton into the cortical actin ring and the concomitant redistribution of TJ proteins to the cell periphery is an inevitable event in endothelial barrier enhancement. Several molecules have been suggested to be important for the formation of the cortical actin ring. Phosphorylated myosin light chain (p-MLC), and its kinase, myosin light chain kinase (MLCK), were observed to be distributed in the cortical region during EC barrier enhancement induced by sphingosine-1-phosphate (S1P), suggesting a potential role for spatially defined MLCK activation in regulating endothelial barrier function. MLC phosphorylation at the cortical region may promote the interaction of actin filaments and myosin, stabilizing the cortical actin ring structures, and thereby increasing the stability of TJ protein complexes in the cell periphery (J Cell Biochem. 2004 Aug. 15; 92(6):1075-85). Cortactin, an F-actin binding protein, has also been implicated in cortical actin rearrangement. Cortactin tyrosine phosphorylation and its translocation to the cortical actin have been associated with enhanced endothelial barrier function (J Biol Chem. 2004 Jun. 4; 279(23):24692-700). Furthermore, phosphorylated cortactin binds to MLCK via its SH3-domain in the cortical ring, implicating that cortactin-MLCK interaction at the site of cortical actin polymerization enhances barrier function by localizing the acto-myosin interaction at an optimal location.
Diabetic retinopathy (DR) is one of the most common vascular retinopathies and a leading cause of legal blindness in working-age adults. The earliest sign of DR is leakage from retinal vessels due to breakdown of the blood-retinal barrier (BRB), which is followed by retinal edema and finally endothelial cell proliferation (N Engl J Med. 2004 Jan. 1; 350(1):48-58). The BRB is a selective endothelial barrier of well-differentiated microvessels of the eye. The disruption of the BRB occurs during the earliest period of vascular retinopathy, which can be recovered before the irreversible angiogenesis characteristic of proliferative vascular retinopathy (Nature. 2005 Dec. 15; 438(7070):960-6). VEGF is known to play an important role in BRB breakdown by altering tight junction integrity and the cytoskeleton organization of endothelial cells, leading to increased permeability during the pathogenesis of DR (Ophthalmic Res. 1995; 27(1):48-52; Nature. 2005 Sep. 22; 437(7058):497-504). Therapies targeting this early and reversible stage of BRB breakdown remain to be developed.
Throughout this application, various publications and patents are referred and citations are provided in parentheses. The disclosures of these publications and patents in their entities are hereby incorporated by references into this application in order to fully describe the present disclosure and the state of the art to which this disclosure pertains.